Project 1. Project 1. An investigation of oligodendroglia in schizophrenia. Demyelinating diseases have been known to be associated with behavioral changes. Recently, the expression levels of several myelin-related genes have been shown to be consistently decreased in postmortem schizophrenic brains compared to controls. Magnetic transfer imaging (MTI) has also shown consistent reduction in myelin content in schizophrenic brains. Diffusion tensor imaging (DTI), which measures the directionality of white matter tracts, has shown a decrease in anisotropy in the brains of schizophrenic patients, suggesting disruptions in white matter tract coherence and directionality in this disease. These data together make a strong case for oligodendrocyte dysfunction in schizophrenia. The anterior cingulate cortex plays a significant role in motivation, attention, and behavior and, as a component of the limbic system, in affect and memory. It has been clearly implicated in schizophrenia by studies of cytoarchitectural postmortem changes and functional imaging showing hypometabolism in this region in schizophrenia. In this project, we propose a quantitative analysis of possible relationships between oligodendrocytic pathology and abnormalities in cytoarchitecture in the cingulate cortex of postmortem brains from schizophrenic patients and neuropathologic and brain imaging analyses of relevant mice mutants such as the Quaking mouse, as well as genetically modified mice such as MAG, RPTPfi, CNPase, or MAGI knock-outs. Our analyses will use advanced microscopy quantitative approaches including the most rigorous stereologic methods for cell counting, estimators of spatial cellular distribution and cytoarchitectural boundaries, as well as single cell morphology by intracellular loading of fluorescent dyes or gene-gun-based DiOlistics techniques. We also are assessing progression of potential changes in white matter integrity using high field magnetic resonance microscopy in vivo at 9.4 T in the relevant mouse models. The combined analysis of human specimens and relevant mice models within the context of this program offers a superb opportunity to investigate myelin deficits that have a clinical impact and to determine the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia. the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia.